Multiple sclerosis (MS) is commonly thought of as an inflammatory demyelinating disease of the CMS white matter. Yet, a growing body of evidence indicates a neurodegenerative component and that the gray matter is affected. Assessment of white matter volume and total parenchyma as a marker of neurodegeneration in MS is potentially contaminated by inflammatory activity and edema that raises the white matter volume. Because gray matter is less prone to fluctuations in volume due to the relative lack of inflammation and edema, gray matter volume may be a more pure, direct, and sensitive marker of neurodegeneration than either white matter volume or total brain volume. We will use magnetic resonance imaging (MRI) and a robust gray matter atrophy analysis method to determine the relationship between gray matter damage and the progressive neurologic and cognitive impairment and to characterize the rate of gray matter atrophy among phenotypes of MS in a three year longitudinal study. The automated atrophy segmentation method should allow a reliable and precise measurement of longitudinal gray matter atrophy. To assess the independent relationship between gray matter atrophy and clinical status, we will account for the influence of general conventional MRI lesion measures, white matter volume, total parenchymal volume, diffuse occult disease (magnetization transfer ratio) in normal appearing brain tissue, and spinal cord atrophy. One potential benefit to the MS scientific field of this line of research is the emergence of automated gray matter volume measurement as a biologic marker/predictor of disease progression and a supportive outcome measure in therapeutic trials of putative neuroprotective agents. By establishing a longitudinal link between gray matter damage and progressive neurologic and cognitive dysfunction we also should gain a better understanding of the structural correlates of impairment. Lay summary: Multiple sclerosis (MS) is traditionally thought of as a disease affecting the white matter of the brain. However, recent research shows that the brain gray matter is also affected. Our goal is to image the gray matter in patients with MS using MRI and determine if the gray matter damage is related to the cognitive impairment and neurologic disability experienced by patients.